EP3982956A1 - Triple pharmaceutical composition for proteinaceous infection - Google Patents
Triple pharmaceutical composition for proteinaceous infectionInfo
- Publication number
- EP3982956A1 EP3982956A1 EP20823121.7A EP20823121A EP3982956A1 EP 3982956 A1 EP3982956 A1 EP 3982956A1 EP 20823121 A EP20823121 A EP 20823121A EP 3982956 A1 EP3982956 A1 EP 3982956A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- protein
- prp
- disease
- amyloid
- atorvastatin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims description 35
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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Definitions
- This disclosure relates to Alzheimer’s disease (AD) therapy.
- AD is commonly believed to be a localized brain disease.
- AD with neurological disease is the third leading cause of death in the United States after cardiovascular diseases and cancer.
- AD normally follows a sequence comprised of neuro-inflammation, amyloid and tau proteopathy, accumulative storage disease, neurotoxicity and neurodamage, loss of function (i.e., activities of daily living (ADL) and cognitive skills), and finally death.
- AD deaths are due to the futility and loss of will to live in these patients who have been depersonalized and lost their appetite for food and liquids, coupled with the failure to thrive leading to premature death usually within five to ten years of diagnosis of AD.
- Amyloid proteins are a large group of proteins of which sixty different types have been described. Thirty-six amyloid proteins have been associated with human disease. Amyloid protein was first seen and described by Rudolf Virchow who thought it was a starchy substance hence the name amyloid related to starch or “amylin” in Latin. It was next thought to be a fatty substance, but later found to be a protein substance. Since the introduction of elegant protein chemistry, mass spectrometry, and x-ray crystallography, amyloid proteins have been better characterized and identified in various human diseases and conditions.
- Amyloid protein disease was once classified as primary or secondary amyloidosis.
- Primary disease was recognized as familial disease with synthesis and deposition of the protein in organs such as the heart, kidney, skin, tongue, fat tissue, and rectum.
- amyloid protein deposition was recognized as secondary to a chronic suppurative condition such as tuberculosis or other uncontrolled bacterial abscess which is common in developing and underdeveloped nations of the world.
- chronic inflammatory conditions such as rheumatoid arthritis and renal dialysis, lead to secondary and reactive amyloid protein deposition.
- APP Amyloid precursor protein
- APP is a trans-membrane protein that penetrates through the neuron’s membrane, and is critical for neuron growth, survival, and post-injury repair. Thus, loss of a neuron’s APP may affect physiological and pathophysiological deficits that contribute to dementia.
- Clinical data from individuals with Down syndrome i.e., trisomy 21 shows that they develop AD earlier in their 30s to 40s, since the gene for APP is in chromosome 21, and they are saddled with three copies. This is akin to patients with inflammatory bowel disease (IBD) who develop colon cancer in their 30- 40s compared to normal population who develop it in their 50s to 80s.
- IBD inflammatory bowel disease
- APP is copied and used to synthesize amyloid protein.
- Amyloid beta is the specific amyloid protein implicated in AD. Amyloid plaques are made up of small peptides, 39-43 amino acids in length. Amyloid beta is produced from the sequential cleavage of APP by beta-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) followed by gamma-secretase. In AD, gamma secretase and beta secretase act together in a proteolytic catabolic reaction, cleaving a smaller fragment of APP. These protein catabolism fragments then form fibrils of amyloid beta, which further form clumps deposited outside the neurons known as senile plaques.
- BACE-1 beta-site amyloid precursor protein-cleaving enzyme 1
- AD Because Ab accumulates excessively in AD, there is a logical inference that its precursor, APP, would be elevated as well. However, a study has shown that neuronal cell bodies contain less APP as a function of their proximity to amyloid plaques. It has been theorized that this APP deficit near AB plaques results from a decline in production of APP which normally rises in response to stress.
- BACE-1 inhibitors, BACE-2 inhibitors and humanized monoclonal antibodies to soluble amyloid protein have been in clinical trials in AD. These trials failed to deliver on the promise of being disease modifying drug (DMD) agents (i.e., they change the underlying pathology of the disease) in AD.
- DMD disease modifying drug
- tau protein deposition hypothesis proposes that tau protein abnormalities initiate the disease cascade.
- hyperphosphorylated tau begins to pair with other threads of tau.
- they form neurofibrillary tangles inside nerve cell bodies
- the microtubules disintegrate, destroying the structure of the cell's cytoskeleton which collapses the neuron's transport system. This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells.
- PrP Prion
- PrP c which is a normally folded protein
- PrP sc a misfolded form which gives rise to the disease.
- the two forms do not differ in their amino acid sequence, however the pathogenic PrP sc isoform differs from the normal PrP c form in its secondary and tertiary structure.
- the PrP sc isoform is more enriched in beta sheets, while the normal PrP c form is enriched in alpha helices.
- PrP sc The differences in conformation allow PrP sc to aggregate with amyl oi dp fibrils and be extremely resistant to protein degradation by enzymes or by other chemical, radiation and physical means.
- the normal form is susceptible to complete proteolysis and soluble in non-denaturing detergents. It has been suggested that pre-existing or acquired PrP sc can promote the conversion of PrP c into PrP sc , which goes on to convert other PrP c . This initiates a chain reaction that allows for its rapid propagation, resulting in the pathogenesis of prion diseases.
- PrP c protein is one of several cellular receptors of soluble amyloid beta (Ab) oligomers.
- Apolipoprotein E transports lipids, fat-soluble vitamins, and cholesterol into the lymph system and then into the blood which is the principal cholesterol carrier in the brain.
- the gene for ApoE is mapped to chromosome 19.
- ApoE is polymorphic with three major alleles: AroE-e2, AroE-e3, and AroE-e4. Although these allelic forms differ from each other by only one or two amino acids at positions, these differences alter ApoE structure and function. These differences have physiological consequences.
- AroE-e4 has an allele frequency of approximately 14 percent and has been heavily implicated in late onset Alzheimer's disease (LOAD).
- the tetracyclines are a very old group of bacteriostatic antibiotics consisting of tetracycline, doxycycline and minocycline. They act by inhibiting protein synthesis in bacterial and protozoa cells and in eukaryotic organism mitochondrion, thereby inhibiting the binding of aminoacyl-tRNA to the mRNA ribosome complex. They do so mainly by binding to the 30S ribosomal subunit in the mRNA translation complex. In addition to inhibiting protein synthesis, these drugs are anti-inflammatory, are lipid soluble, and have high central nervous system concentration.
- Sirolimus also known as rapamycin, is a macrolide compound marketed under the trade name Rapamune® by Pfizer. There are numerous rapamycin derivatives (rapalogs) that function as mTOR inhibitors. New rapalogs continue to be researched and developed every day. Sirolimus has immunosuppressant effects in humans and is used in preventing the rejection of kidney transplants. It inhibits activation of T cells and B cells by reducing their sensitivity to interleukin-2 (IL-2) through mTOR inhibition. By its effect on B cells it prevents the humoral immune system from synthesizing humoral antibodies to the renal graft. Sirolimus and its rapalogs increase autophagy and mitophagy.
- Rapamune® rapamycin derivatives
- FIG. 1 is a skeletal formula of tetracycline with atoms and four rings numbered and labeled.
- FIG. 2 is a formula for doxycycline.
- FIG. 3 is a formula for minocycline.
- FIG. 4 is a formula for sirolimus.
- FIG. 5 is a conceptual diagram showing the basis for exponential growth of the presence of Ab and PrP sc .
- AD is not a localized brain disease.
- AD is a prion protein complex infection, and a systemic disease involving both the body and the peripheral circulation and B-cells.
- AD includes a localized reaction in the neocortex. Indeed, proof of this is the fact that AD can be diagnosed in saliva by testing for Ab42 level (with ELISA test), blood Ab42 / 4o ratio, and cerebrospinal Ab42 level. Additionally, AD can be initiated by inflammation of the brain caused by other diseases such as Parkinson’s Disease and Chronic traumatic encephalopathy (CTE) from repeated brain trauma such as in boxers and footballers.
- CTE Chronic traumatic encephalopathy
- Amyloid beta protein deposition seen in AD is secondary to a chronic neuro- inflammatory condition in the acetylcholine discharging neurons of the cerebral cortex. This amyloid protein deposition starts ten to fifteen years prior to the clinical diagnosis of AD in the patient and continues until the patient dies.
- the transcription of the APP gene and the RNA transcript are the rate-limiting steps and are most susceptible for blockage and control of the process of amyloid protein formation.
- tRNA transcript RNA
- cmRNA messenger RNA
- This neuroinflammation in the neocortex is concomitant with localized secretion of amyloid beta to the acetylcholine secreting memory nerve fibers, and the secretion of cellular prion protein (PrP c ) peptides and tau protein peptides. Because of the neurotoxicity of the amyloid protein oligomers there is the misfolding of the PrP c peptides converting them from an alpha helical structure to a beta helical structure (i.e., PrP sc ).
- PrP sc beta helical structure interacts with AB fibrils and starts laying down sheets of AB fibrils which are neurotoxic and lead to neurotoxicity and nerve fiber and nerve cell death creating the pathognomonic amyloid plaques and the tau protein tangles.
- FIG. 5 demonstrates the basis for exponential growth of the presence of AB and PrP sc in AD.
- PrP sc when PrP sc is applied to PrP c , the PrP c misfolds into PrP sc .
- APP and AB AB is a seed for producing more AB from APP.
- these two cycles are not independent. They are interdependent. That is, AB seeds conversion of PrP c into PrP sc , and PrP sc seeds production of AB from APP.
- AD may be treated and prevented through two treatment forms.
- Amyloid beta protein present in the blood, diffuses into the cerebrospinal fluid which washes over the brain and the neocortex. This creates a secondary neocortical reaction with the laying of sheets of amyloid beta fibrils, leading to the death and destruction of memory cells and creating amyloid plaques and neurofibrillary tau protein tangles.
- One treatment form uses an immunosuppressant to address the systemic humoral B cell reaction and prion protein transcription, translation and synthesis.
- the other treatment form uses an antibiotic to address synthesis of amyloid beta protein. Benefits are obtained by combining the treatment forms.
- AD arises from a complex of rogue prion proteins— a witch’s brew.
- This rogue prion protein complex consists of AB fibrils and prion receptor protein (PRP) b (PrP sc ) fibrils.
- PRP prion receptor protein
- the body’ s natural reaction to the rogue prion protein complex is a self-defense mechanism that itself harms tissue.
- These defense mechanisms take the form of a self-assembling Pacman which attacks and eats the rogue prion protein complex.
- Injury to the corresponding tissue is the culprit in the pathogenesis of AD and other prion protein complex infections.
- the systemic disease component of AD may be treated with an immunosuppressant such as sirolimus.
- Sirolimus by its effect on B cells, impairs the humoral immune system from synthesizing humoral antibodies and APP. This abrogates the systemic component of the AD pathogenesis.
- sirolimus is only prescribed to patients that undergo transplants, and certain cancers. There is no indication for combining sirolimus with a tetracycline.
- Sirolimus also inhibits antibody formation and abrogates synthesis of amyloid beta protein by plasma cells and B cells in general. It also suppresses the innate immune system and the cytokines produced by microglia and macrophages such as TNFa, IL-Ib, IL-6, and gamma interferon.
- the central nervous system (CNS) localized effects of AD may be treated with antibiotics such as tetracyclines.
- Tetracyclines block protein synthesis by their effects on transcription, translation, and binding to the ribosomal protein complexes.
- the tetracycline compounds can deal with the CNS/neocortical component of the AD pathogenesis by inhibiting the transcription of the APP gene on chromosome 21 and the transcription of the PrP gene on chromosome 20. Additionally, the tetracyclines block translation of the gene and protein synthesis by binding to the 30S and 50S subunits of the ribosomal protein complex.
- AD patients may be characterized as three types. In Type I, the patient has Down’s Syndrome, and this is approximately 0.001% of all AD cases. In Type I patients, AD manifests at about 30-40 years of age. Its genetic marker is Trisomy 21. In Type II, the patient has early onset Alzheimer’s disease (EOAD), and this is approximately 1-5% of all AD cases. In Type II patients, AD manifests at about 50-60 years of age. Its genetic marker is PSEN1 and PSEN2 on Chromosome 14 and 1 respectively. In Type III, the patient has late onset Alzheimer’s disease (LOAD), and this is approximately 95% of all AD cases. In Type III patients, AD manifests at about 65-90 years of age. Two-thirds of patients with Type III are APOE e4 positive and APOE e4 is located on chromosome 19. Type III patients may be further distinguished as either being APOE e4 positive or APOE e4 negative.
- Type III APOE e4 positive produces a defective Apolipoprotein E (ApoE) protein.
- ApoE Apolipoprotein E
- This defective protein makes it harder for the body to metabolize proteins, fats, and lipids, and it makes it harder for the body to send nutrients and cholesterol to the brain.
- APOE e4 positive patients are hit harder when they develop AD, compared to Type III AD patients that still produce functioning APOE (APOE e4 negative).
- Appropriate therapies may depend on the characterization of AD a patient has. All types will benefit from a combination of an antibiotic such as tetracycline with an immunosuppressant such as sirolimus. Patients with Type III that are APOE e4 positive should also receive a lipophilic statin such as Atovar (Atorvastatin), which crosses the blood brain barrier.
- an antibiotic such as tetracycline
- an immunosuppressant such as sirolimus.
- Patients with Type III that are APOE e4 positive should also receive a lipophilic statin such as Atovar (Atorvastatin), which crosses the blood brain barrier.
- a dose may take the form of a unit dose. That is, a unit dose is a pill, a tablet or a capsule— one and only one.
- an appropriate therapy may be one of the following: (a) 50 mg tetracycline, 1 mg sirolimus, 10 mg atorvastatin; (b) 50 mg tetracycline, 1 mg sirolimus, 20 mg atorvastatin; (c) 100 mg tetracycline, 1 mg sirolimus, 40 mg atorvastatin; (d) 100 mg minocycline, 1 mg sirolimus, 80 mg atorvastatin; (e) 50 mg tetracycline, 2 mg sirolimus, 10 mg atorvastatin; (f) 50 mg tetracycline, 2 mg sirolimus, 20 mg atorvastatin; (g) 100 mg tetracycline, 2 mg sirolimus, 40 mg atorvastatin; (h) 100 mg minocycline, 2 mg sirolimus, 80 mg atorvastatin; (i) 2 mg sirolimus 100 mg minocycline and 20 mg atorvastatin.
- atorvastatin dosages of atorvastatin may be given twice during the day for example to achieve a 20 mg dose a patient may take 10 mg atorvastatin in the morning and 10 mg atorvastatin at another time.
- the tetracyclines listed above may be either minocycline or doxycy cline. Other oral or intravenous tetracyclines may also be used. Simvastatin and Lovastatin which are both lipophilic may also be used.
- statin effects on cholesterol and triglyceride levels in the patient should be aware of statin effects on cholesterol and triglyceride levels in the patient.
- atorvastatin may be swapped out for another statin listed above.
- the dosage of the new statin may be either the same as atorvastatin or adjusted based on the effects of the statin.
- the dosage of statin or atorvastatin may be further adjusted slightly to account for a patient’s blood chemistry and neurological effects.
- a three drug medication including minocycline or doxycycline, sirolimus and atorvastatin
- different medications with different atorvastatin dosages may need to be manufactured and distributed to patients with certain diseases.
- a pill containing the three drugs may contain 50 mg minocycline, 1 mg sirolimus and 40 mg atorvastatin, but for patients already suffering from high cholesterol and AD, another pill containing 50 mg minocycline, 1 mg sirolimus, and 80 mg atorvastatin may needed.
- a lower atorvastatin dosed pill may be produced such as 50 mg minocycline, 1 mg sirolimus, and 20 mg atorvastatin.
- Effectiveness of the therapy described herein may be apparent in as little as 72 hours. Other times effectiveness may be seen in three to twelve months.
- the patient may discontinue the therapy under controlled observation for relapse and possible retreatment or continue on a maintenance dose.
- effectiveness may be measured by the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog) subscale and the Alzheimer’s Disease Cooperative Study-Activities of Daily Life (ADCS-ADL) scale or the Mini- Mental Status Examination (MMSE). Both of these tests have been developed over many years, and it is expected that they will continue to be refined.
- How often the medications are taken may be varied, as may the time of day.
- Every day or every other day may be sufficient for some patients, or three days on and two days off. These are examples of drug holidays. Dosage may be different day-to-day. Time of day for taking the medication may be selected based upon the patient having an empty stomach for better absorption.
- Drugs in the therapy may be administered together, separately, or at least one separately and at least some together.
- Drugs in the therapy may be administered orally (e.g. tablets), topically (e.g. patches), intranasally (e.g. inhalation) or parenterally such as by immediate acting formulation or by sustained release formulations, half-life extended injectable formulations, or at least one sustained release formulation, and at least one half-life extended injectable formulation.
- the dosage levels may be varied, with daily dosages of doxycycline as low as 40 mg, minocycline as low as 25 mg, and sirolimus as low as 0.5 mg. On the upper end the dosages may be as much as 400 mg (e.g., 200 mg twice per day) of doxycycline, 300 mg (e.g., 150 mg twice per day) of minocycline, and 4 mg (e.g., 2 mg twice per day) of sirolimus.
- the dosages specified above are for an average adult, and dosage may be correlated to body weight, with heavier patients receiving a larger dose and lighter patients receiving a smaller dose. Dosages need not be correlated to age. Dosages may be slow release.
- Progressive dose escalation may be utilized with tetracyclines, immunosuppressants, and statins. Progressive dose escalation may be used either to make the therapy more potent or alleviate adverse side effects caused by the drugs, or cause the side effects to appear later in the treatment thus reducing patient discomfort. Treatments listed may be modified by progressive dose escalation. Progressive dose escalation may be across days or weeks, such as 25% of the full dosage on the first day or week, 50% the second, 75% the third, and 100% thereafter. Other progressive dose escalations may take the form of 50% dosage for an initial period then 100% later.
- Tetracyclines used may either be synthetic, semi synthetic, or naturally occurring. Additionally, if more synthetic tetracyclines are invented in the future, those tetracyclines would likely be useful as well because of the common basic structure of all tetracyclines.
- tetracyclines may be used: chlortetracy cline, oxytetracy cline, demeclocy cline, lymecycline, meclocycline, methacycline, minocycline, rolitetracycline, glycecyclines, tigecycline, omadacy cline, sarecy cline, and eravacy cline.
- immunosuppressants may be used that block B cell function and synthesis of amyloid beta and PrP sc , such as are cyclosporin, tacrolimus and everolimus. Macrolides may also be used. Appropriate macrolides include, azithromycin, clarithromycin, erythromycin, fidaxomicin, telithromycin. Other immunosuppressants may also be used including Corticosteroids, Janus kinase inhibitors, calcineurin inhibitors mTOR inhibitors, IMDH inhibitors, biologies, and monoclonal antibodies.
- Statins may be used for patients that have Type III and are APOE e4 positive.
- Appropriate statins include atovar, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, fenofibric acid, alirocumab, etravirine, cyproterone, posaconazole, ticagrelor, bezafibrate, coenzyme Q-10 colesevelam, rosuvastatin, simvastatin, simvastatin + ezetimibe, lovastatin + niacin extended-release, atorvastatin + amlodipine, and simvastatin + niacin extended-release.
- a three drug approach may be necessary for certain patients undergoing AD therapy.
- Patients may require a therapy consisting of minocycline, sirolimus, and atorvastatin.
- Atorvastatin is also known as Lipitor®.
- the dosage of atorvastatin can range from 1 mg - 100 mg.
- An appropriate dosage may include 50 mg minocycline, 1 mg sirolimus, and 10 mg atorvastatin.
- the range of other statin may be .01 mg -200 mg.
- cerivastatin an appropriate dosage would be severely less, such as .8 mg cerivastatin, 50 mg minocycline, and 1 mg sirolimus.
- Patient A is a 54 year old APO E 4 positive E3/E4 male who suffered from AD for five years prior to treatment.
- Patient A had trouble forming complete sentences and required the aid of a chart with pictures to communicate.
- For basic functions such as eating or going to the bathroom the patient would have to make hand gestures or point to pictures demonstrating activities on a chart.
- Patient A showed extreme signs of frustration, and on occasions acted out when caregivers could not understand him.
- Patient A also had trouble completing simple tasks.
- Patient A could not tie his own shoes and often fumbled several times with doorknobs when trying to open a door.
- the word recall test adapted from the Alzheimer’s Disease Assessment Scale was performed prior to treatment. The patient could not remember or communicate any words from the test.
- Patient A was treated with 2 mg sirolimus and 100 mg minocycline and 20mg atorvastatin once a day for four months.
- Patient A experienced recovery of speech and could form short phrases and sometimes complete entire sentences.
- Patient A’ s use of a picture chart increased, and he became less frustrated and acted out to caregivers less.
- Patient A experienced resolved aphasia, improved short term memory and improved long term memory.
- the word recall test adapted from the Alzheimer’s Disease Assessment Scale was performed and the patient could remember up to five words.
- Patient B is a 65 year old APO E 4 positive male suffering from AD.
- Patient B had trouble with everyday tasks such as getting dressed, remembering to eat meals, communicating with caregivers, and remembering his family members. Often times when buttoning his shirt, he would forget to button buttons or misalign buttons. He would forget articles of clothing such as socks or undergarments and had trouble putting on shoes. A caregiver would have to prepare meals and remind Patient B to eat them.
- Patient B also had difficulty remembering why caregivers were in his home and would inquire as to their identity constantly. Patient B could remember and engage in conversation with his children, but midway through conversations would often ask his children who they were as if they were strangers.
- the word recall test adapted from the Alzheimer’ s Disease Assessment Scale was performed prior to treatment. Patient B was able to remember one word each of the three times the test was administered.
- Patient B was treated with 2 mg sirolimus 100 mg minocycline and 20 mg atorvastatin once a day for two months.
- Patient B experienced improvements to short term memory and improvements to long term memory.
- Patient B stopped missing buttons and could dress himself perfectly.
- Patient B did not forget meals his caregivers prepared for him. The inquiry into who his children and caregivers were occurred with less frequency.
- the word recall test adapted from the Alzheimer’s Disease Assessment Scale was performed after treatment Patient B could recall up to 4 words.
- Alzheimer’s Disease is a complex disease that presents several druggable targets including a. Intracerebral amyloidosis, b. systemic amyloidosis, c. APO E4 and lipid dysmetabolism in astrocytes and microglia in CNS, d. cerebral neuroinflammation, f. systemic inflammation by Tumor Necrosis Factor alpha and Interleukin 1 b and IL 6. These targets call for combination drug therapy. At the simplest AD Therapy can be simplified to two-Drug therapy for APO E4 Negative (E2/E3) AD and three-Drug Therapy for APO E4 positive AD.
- “plurality” means two or more.
- a“set” of items may include one or more of such items.
- the terms“comprising”,“including”,“carrying”,“having”,“containing”,“involving”, and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases“consisting of’ and“consisting essentially of’, respectively, are closed or semi-closed transitional phrases with respect to claims.
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- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
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- Communicable Diseases (AREA)
- Oncology (AREA)
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Abstract
Description
Claims
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201962861855P | 2019-06-14 | 2019-06-14 | |
US16/504,723 US20200000829A1 (en) | 2018-06-27 | 2019-07-08 | Therapy and prevention of prion protein complex infections |
US16/565,242 US10729705B2 (en) | 2018-06-27 | 2019-09-09 | Therapy and prevention of prion protein complex infections in non-human animals |
PCT/US2020/037787 WO2020252475A1 (en) | 2019-06-14 | 2020-06-15 | Triple pharmaceutical composition for proteinaceous infection |
Publications (3)
Publication Number | Publication Date |
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EP3982956A1 true EP3982956A1 (en) | 2022-04-20 |
EP3982956A4 EP3982956A4 (en) | 2023-05-03 |
EP3982956B1 EP3982956B1 (en) | 2024-06-12 |
Family
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Family Applications (1)
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EP20823121.7A Active EP3982956B1 (en) | 2019-06-14 | 2020-06-15 | Triple pharmaceutical composition for proteinaceous infection |
Country Status (13)
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EP (1) | EP3982956B1 (en) |
JP (1) | JP2022537132A (en) |
KR (1) | KR20220020832A (en) |
CN (1) | CN114007609A (en) |
BR (1) | BR112021025253A2 (en) |
CA (1) | CA3142164A1 (en) |
DK (1) | DK3982956T3 (en) |
FI (1) | FI3982956T3 (en) |
LT (1) | LT3982956T (en) |
MX (1) | MX2021015266A (en) |
PT (1) | PT3982956T (en) |
SG (1) | SG11202113265PA (en) |
WO (1) | WO2020252475A1 (en) |
Family Cites Families (7)
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US7189703B2 (en) * | 1998-01-09 | 2007-03-13 | Intracell, Llc | Treatment and diagnosis of alzheimer's disease |
CA2499599A1 (en) * | 2002-09-17 | 2004-04-01 | New York University | Methods of treating age associated memory impairment (aami), mild cognitive impairment (mci), and dementias with cell cycle inhibitors |
JP2007532624A (en) * | 2004-04-14 | 2007-11-15 | ワーナー−ランバート カンパニー リミテッド ライアビリティー カンパニー | Therapeutic combinations for the treatment of Alzheimer's disease |
US20140271923A1 (en) * | 2013-03-14 | 2014-09-18 | Christopher Brian Reid | Compositions & formulations for preventing and treating chronic diseases that cluster in patients such as cardiovascular disease, diabetes, obesity, polycystic ovary syndrome, hyperlipidemia and hypertension, as well as for preventing and treating other diseases and conditions |
EA201700052A1 (en) * | 2014-08-18 | 2017-06-30 | Фабризио Де Силвестри | APPLICATION IN ONE PILLE, TABLET, CAPSULE MINOCYCLINE, ACYCLOGUANOSINE, ATORVASTATIN AND VITAMIN D FOR THE TREATMENT OF RHEUMATOID ARTHRITIS |
DE102016208567A1 (en) * | 2016-05-19 | 2017-11-23 | Heraeus Medical Gmbh | Polymer solution for viscous supplementation |
US10350226B1 (en) * | 2018-06-27 | 2019-07-16 | Joshua O. Atiba | Therapy and prevention of prion protein complex infections |
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2020
- 2020-06-15 LT LTEPPCT/US2020/037787T patent/LT3982956T/en unknown
- 2020-06-15 WO PCT/US2020/037787 patent/WO2020252475A1/en active Application Filing
- 2020-06-15 JP JP2021573291A patent/JP2022537132A/en active Pending
- 2020-06-15 BR BR112021025253A patent/BR112021025253A2/en unknown
- 2020-06-15 DK DK20823121.7T patent/DK3982956T3/en active
- 2020-06-15 CN CN202080042131.XA patent/CN114007609A/en active Pending
- 2020-06-15 EP EP20823121.7A patent/EP3982956B1/en active Active
- 2020-06-15 MX MX2021015266A patent/MX2021015266A/en unknown
- 2020-06-15 KR KR1020217041835A patent/KR20220020832A/en unknown
- 2020-06-15 CA CA3142164A patent/CA3142164A1/en active Pending
- 2020-06-15 SG SG11202113265PA patent/SG11202113265PA/en unknown
- 2020-06-15 FI FIEP20823121.7T patent/FI3982956T3/en active
- 2020-06-15 PT PT208231217T patent/PT3982956T/en unknown
Also Published As
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PT3982956T (en) | 2024-07-26 |
DK3982956T3 (en) | 2024-07-22 |
EP3982956A4 (en) | 2023-05-03 |
MX2021015266A (en) | 2022-01-18 |
KR20220020832A (en) | 2022-02-21 |
CN114007609A (en) | 2022-02-01 |
LT3982956T (en) | 2024-08-26 |
EP3982956B1 (en) | 2024-06-12 |
BR112021025253A2 (en) | 2022-04-12 |
FI3982956T3 (en) | 2024-08-06 |
WO2020252475A1 (en) | 2020-12-17 |
JP2022537132A (en) | 2022-08-24 |
CA3142164A1 (en) | 2020-12-17 |
SG11202113265PA (en) | 2021-12-30 |
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